Hepatocyte growth factor (HGF), also known as scatter factor (SF), is a growth factor which is involved in various physiological processes, such as wound healing and angiogenesis. The high affinity interaction of HGF interaction with its receptor (c-Met) is implicated in tumour growth, invasion and metastasis.
Knudsen et al have reviewed the role of HGF and c-Met in prostate cancer, with possible implications for imaging and therapy [Adv. Cancer Res., 91, 31-67 (2004)]. Labelled anti-met antibodies for diagnosis and therapy are described in WO 03/057155.
c-Met has been shown to be involved in tumour growth, invasion and metastasis in many human cancers of epithelial origin. c-Met is expressed by most carcinomas and its elevated expression relative to normal tissue has been detected in many cancers, including: lung, breast, colorectal, pancreatic, head and neck, gastric, hepatocellular, ovarian, renal, glioma, melanoma and a number of sarcomas. In colorectal carcinoma (CRC), over-expression of c-Met has been detected in dysplastic aberrant crypt foci, the earliest pre-neoplastic lesions of the disease. In head and neck squamous cell cancer, c-Met is reportedly expressed or overexpressed in roughly 80% of primary tumours. In prostate cancer metastasis to bone, c-Met was reported overexpressed in over 80% of bone metastasis.
Under normal conditions, c-Met is expressed on epithelial cells and activated in a paracrine fashion, by mesenchymally derived HGF. The activation of c-Met in normal cells is a transient event and is tightly regulated. In tumour cells, however, c-Met can be constitutively active. In cancer, aberrant c-Met stimulation can be achieved through c-Met amplification/over-expression, activating c-Met mutations (e.g. structural alterations) and acquisition of autonomous growth control through creation of autocrine signalling loops. In addition, a defective down-regulation of the c-Met receptor will also contribute to aberrant c-Met expression in the cell membrane. While the over-expression of c-Met is HGF dependent (autocrine/paracrine), structural alterations caused by mutations are HGF independent (e.g. loss of extracellular domain).
WO 2004/078778 discloses polypeptides or multimeric peptide constructs which bind c-Met or a complex comprising c-Met and HGF. Approximately 10 different structural classes of peptide are described. WO 2004/078778 discloses that the peptides can be labelled with a detectable label for in vitro and in vivo applications, or with a drug for therapeutic applications. The detectable label can be: an enzyme, a fluorescent compound, an optical dye, a paramagnetic metal ion, an ultrasound contrast agent or a radionuclide. Preferred labels of WO 2004/078778 are stated to be radioactive or paramagnetic, and most preferably comprise a metal which is chelated by a metal chelator. WO 2004/078778 states that the radionuclides therein can be selected from: 18F, 124I, 125I, 131I, 123I, 77Br, 76Br, 99mTc, 51Cr, 67Ga, 68Ga, 47Sc, 167Tm, 141Ce, 111In, 168Yb, 175Yb, 140La, 90Y, 88Y, 153Sm, 166Ho, 165Dy, 166Dy, 62Cu, 64Cu, 67Cu, 97Ru, 103Ru, 186Re, 203Pb, 211Bi, 212Bi, 213Bi, 214Bi, 105Rh, 109Pd, 117mSn, 149Pm, 161Tb, 177Lu, 198Au and 199Au. WO 2004/078778 states (page 62) that the preferred radionuclides for diagnostic purposes are: 64Cu, 67Ga, 68Ga, 99mTc and 111In, with 99mTc being particularly preferred.
WO 2004/078778 teaches at Examples 14-17 methods of increasing the serum residence time of the c-Met binding peptides: conjugation to a moiety which binds non-covalently to human serum albumin; conjugation to PEG; fusion to serum protein and conjugation to maleimide.
WO 2009/016180 discloses imaging agents which comprises a conjugate of Formula I:
                where:        Z1 is attached to the N-terminus of cMBP, and is H or MIG;        Z2 is attached to the C-terminus of cMBP and is OH, OBc, or MIG,                    where Bc is a biocompatible cation;                        cMBP is a cMet binding cyclic peptide of 17 to 30 amino acids which comprises the amino acid sequence (SEQ-1):        Cysa-X1-Cysc-X2-Gly-Pro-Pro-X3-Phe-Glu-Cysd-Trp-Cysb-Tyr-X4-X5-X6;        wherein X1 is Asn, His or Tyr;                    X2 is Gly, Ser, Thr or Asn;            X3 is Thr or Arg;            X4 is Ala, Asp, Glu, Gly or Ser;            X5 is Ser or Thr;            X6 is Asp or Glu;            and Cysa-d are each cysteine residues such that residues a and b as well as c and d are cyclised to form two separate disulfide bonds;                        MIG is a metabolism inhibiting group;        L is a synthetic linker group;        BzpM is a benzopyrylium dye.        
WO 2008/139207 discloses cMet binding cyclic peptide similar to those of WO 2009/016180, in this case labelled with a particular class of cyanine dyes.
The optical imaging agents of WO 2009/016180 and WO 2008/139207 are said to be useful for optical imaging to obtain images of sites of c-Met over-expression or localisation in vivo, particularly for imaging colorectal cancer.